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Background: MicroRNAs (miRNAs, miRs) are involved in most physiological, developmental, and pathological processes. miR-192 and miR-205 are expressed preferentially in the renal cortex and closely relevant to the renal cell biology. In the present study, we aim to measure the serum levels of miR-192 and miR-205 and their correlation with clinicopathological data in patients with primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). Methods: Fifty-six patients (35 male, 21 female) with idiopathic nephrotic syndrome (FSGS 30, MCD 26) and 20 healthy controls were enrolled in the study. We quantified the serum levels of miR-192 and miR-205 in patients with FSGS and MCD by RT-qPCR. Results: Patients with FSGS had higher serum levels of miR-192 and miR-205 than those with MCD (324.49 ± 42.74 fmol/l versus 90.19 ± 27.14 fmol/l, p < 0.01, 2.25 ± 0.69 fmol/l versus 0.60 ± 0.51 fmol/l, p < 0.01, respectively). The level of miR-192 was positively correlated with the proteinuria in patients with FSGS and MCD ( r = 0.62, p < 0.001, r = 0.84, p < 0.001, respectively). Similarly, the level of miR-205 was positively correlated with the proteinuria in patients with FSGS ( r = 0.54, p = 0.002). In addition, the serum level of miR-192 was significantly correlated with the degree of interstitial fibrosis in patients with FSGS ( r = 0.342, p < 0.05). Conclusions: miR-192 and miR-205 have the potential as markers to differentiate FSGS from MCD. [ABSTRACT FROM AUTHOR]

Background: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. Methods: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. Results: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1–2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16–3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. Conclusions: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children. [ABSTRACT FROM AUTHOR]

Ferroptosis is a non-apoptotic form of cell death, involved in chronic kidney diseases (CKD) and acute kidney injury (AKI), so far, the role of ferroptosis in focal segmental glomerulosclerosis (FSGS) remains largely unknown. We aimed to investigate the role of ferroptosis in FSGS, in this study, we found the reduced expression of GPX4 in podocytes, as well as tubular epithelial cells (TECs), from patients with FSGS. Treatment with ferrostatin-1 (Fer-1), a potent and selective ferroptosis inhibitor, significantly reduced proteinuria, prevented glomerulosclerosis, attenuated podocyte injury in ADR-induced FSGS murine model. As expected, ADR treatment caused downregulation of GPX4 in human podocytes, treatment with Fer-1 greatly blocked the downregulation of GPX4, restored the GSH level and attenuated cell death. Furthermore, Fer-1 treatment greatly delayed the development of tubulointerstitial fibrosis in ADR-induced FSGS murine model. Taken together, ferroptosis is involved in the pathogenesis of FSGS, targeting ferroptosis is a promising therapeutic option for patients with FSGS. • Podocyte expression of GPX4 was downregulated in FSGS patients as comparing with healthy controls. • Treating ADR mice with the ferroptosis inhibitor Fer-1 blocked the development of proteinuria and glomerulosclerosis, protected podocyte from ADR injury. • Inhibition of ferroptosis by Fer-1 significantly delayed tubulointerstitial fibrosis in ADR-treated nephropathy. [ABSTRACT FROM AUTHOR]

Aim: Glomerular microthrombosis (GMT) was a common vascular lesion in patients with lupus nephritis (LN). The objective of this study was to investigate the relationship between serum anti‐beta2‐glycoprotein I antibodies (a‐β2GP1) and anti‐complement 1q antibodies (a‐C1q) antibodies and to investigate the possible mechanism of GMT in children with LN. Methods: The subjects were 191 children with LN diagnosed by renal biopsy in our hospital from January 2017 to January 2020. The patients were divided into GMT group and non‐GMT group. The clinical manifestations, laboratory tests, renal pathology, prognosis of the two groups and the relationship between a‐β2GP1 and a‐C1q antibodies were observed. Results: In 191 children with LN, 52 cases (27.23%) presented with GMT. The value of C3, haemoglobin (Hb), estimate glomerular filtration rate (eGFR) and anticardiolipin antibody (ACA) in GMT group were lower than that of non‐GMT group (p <.05, p <.01). The value of serum creatinine (Scr), 24 h proteinuria (PRO), urine red blood cells (RBC), N‐acetyl‐β‐d‐glucosidase (NAG) and retinol‐binding protein (RBP), a‐C1q, a‐β2GP1, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and renal histopathological activity index (AI) score in GMT group were higher than that of non‐GMT group (p <.05, p <.01). The positive proportions of serum a‐C1q and a‐β2GP1 in GMT group were higher than those in non‐GMT group (p <.05). According to Spearman correlation analysis, a‐C1q was positively correlated with AI score, SLEDAI, a‐β2GP1, GMT, LN‐III and LN‐IV. Hb, eGFR and a‐C1q Ab were associated with the formation of GMT in children with LN. The complete proteinuria remission and renal survival in GMT group were significantly lower than those in non‐GMT group (p <.05, p <.01). Conclusion: LN children with GMT had more severe clinical manifestations and renal pathologic damages, and poor outcome. Serum a‐C1q level was positively correlated with a‐β2GP1, and a‐β2GP1 may be involved in the formation of GMT in children with LN, which might involve in the activation of complement classical pathway. [ABSTRACT FROM AUTHOR]

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a class of systemic autoimmune diseases, results in damage of various critical organs including kidneys, lungs, eyes, and nervous system. MicroRNA-340-5p was confirmed to be downregulated in autoimmune pathogenesis. However, the role of miR-340-5p remains unknown in ANCA-induced glomerulonephritis (GN). The current study aimed to explore the role of miR-340-5p in ANCA-induced GN. The animal models of ANCA-induced GN was established by experimental autoimmune vasculitis (EAV) operation. The primary glomerular endothelial cells (PGEnCs) were treated with anti-myeloperoxidase (anti-MPO) to mimic cell injury in vitro. The renal function was analysed by measuring serum creatinine, blood urea nitrogen, urine blood, urine protein and urine leukocytes. The levels of RNA and proteins were examined by RT-qPCR and western blot analysis, respectively. The binding capacity between miR-340-5p and KDM4C was detected by luciferase reporter assay. Cell apoptosis was analysed by flow cytometry in vitro. Cell viability was determined by CCK-8 assay. The cleaved caspase-3 activity was analysed by immunofluorescent assay. Cell inflammation was measured by western blot. Cell procoagulant activity was assessed by FXa generation assay. The histological changes of renal tissues were assessed by Haematoxylin and eosin (H&E) staining assay. The correlation between miR-340-5p and KDM4C level (or content of TNF-α and IL-6) was analysed by Pearson correlation analysis. The injection of anti-MPO IgG induced a significant elevation of Serum creatinine and blood urea nitrogen in serum, as well as urine blood, urine protein and urine leukocytes. Importantly, KDM4C was downregulated in model group. In mechanism, we identified that miR-340-5p bound with KDM4C 3'untranslated region (UTR), negatively regulated KDM4C in endothelial cells and negatively correlated with KDM4C in serum of GN rats. In function, we found that miR-340-5p promoted B cell activation and proliferation by downregulating KDM4C. The in vitro assays showed that the decrease of cell viability induced by anti-MPO was reversed by miR-340-5p overexpression, and further reduced by KDM4C overexpression. Inversely, the suppressive effects of miR-340-5p mimics on cell apoptosis, cleaved caspase-3 activity, inflammatory response and pro-coagulation were countervailed by KDM4C overexpression in anti-MPO-treated cells. The in vivo assays validated that miR-340-5p overexpression mitigated the impairment of renal function, and histological changes induced by anti-MPO IgG injection in model group. Finally, we found the negative correlation between miR-340-5p and TNF-α (or IL-6) content in serum of GN rats. In conclusion, we found that miR-340-5p inhibited endothelial apoptosis and inflammatory response by targeting KDM4C in ANCA-mediated GN through activation of B cells, implying a potential novel insight for treatment of ANCA-mediated GN. [ABSTRACT FROM AUTHOR]

The emerging technology of urinary proteomics has become an efficient biological approach for identifying biomarkers and characterizing pathogenesis in renal involvement. In this study, we attempted to elucidate the relationship between IgAN and HSPN in children, employing LC-MS/MS to perform urinary proteomic analyses using the DIA method. Early-morning spot urine was collected from patients with biopsy-proven IgAN (n = 19) and HSPN (n = 19) prior to treatment and renal biopsy in the Department of Pediatrics, Jinling Hospital, Nanjing, China, and did healthy volunteers (n = 14), from June 2018 to December 2019. Two hundred seventy-six urinary proteins and 125 urinary proteins were determined to be differentially expressed in children with IgAN (n = 4) and HSPN (n = 4), respectively, compared to the urinary proteins of healthy children (n = 4) (p < 0.05). GO analysis demonstrated that the differentially expressed proteins of the two groups, which were located in the extracellular matrix and cell membrane, were primarily involved in biological processes, including metabolic processes, immune system processes, cellular adhesion, cell proliferation, signaling, and biological regulation. KEGG analysis revealed that the differentially expressed proteins of the two groups were associated with cell adhesion molecules, ECM-receptor interactions, the PI3K-Akt signaling pathway, the complement and coagulation cascades, regulation of actin cytoskeleton, cholesterol metabolism, and platelet activation. The target proteins (alpha-1B-glycoprotein (A1BG) and afamin (AFM)), which participated in the complement and coagulation cascades and the regulation of complement activation, were further investigated in the independent validation cohort by ELISA. These proteins were significantly increased in children with IgAN (n = 15) and HSPN (n = 15) compared with the proteins observed in healthy controls (n = 10, P < 0.05). The validated results were consistent with the mass spectrometry results. IgAN and HSPN both result from the glomerular deposition of abnormally glycosylated IgA1 with mesangial proliferative changes, and both diseases are common glomerulopathies in the pediatric population that are believed to be correlated. Interestingly, our data, by combining urinary proteomic analyses, showed that several uniform enrichment pathways played an important role in the progression of IgAN and HSPN, suggesting that we might reduce the renal involvement of the two diseases in children through these pathways. The same urinary proteins along these pathways were observed to be differentially expressed in children with IgAN and HSPN, implying that these proteins may be potential biomarkers to identify the two diseases. Future studies examining larger cohorts are warranted to confirm the validity of our findings. Unlabelled Image • The biological relationship between IgAN and HSPN in children from urinary proteomics. • The differentially expressed proteins in children with IgAN and HSPN • Several common signaling pathways were associated with renal involvement. • Potential biomarkers along the pathways of IgAN and HSPN in children • The target proteins (A1BG and AFM) were chosen for validation by ELISA. [ABSTRACT FROM AUTHOR]

Sox9 is important for multiple aspects of development, such as testis, pancreas and heart development. Previous studies have reported that Sox9 induced epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) production in organ fibrosis and associated diseases, such as vascular calcification. However, to the best of our knowledge, the role and underlying mechanism of action of Sox9 in renal fibrogenesis remains unknown. The results of the present study revealed that Sox9 expression levels were upregulated in the tubular epithelial cells of a rat model of obstructive nephropathy. Furthermore, the overexpression of Sox9 in NRK-52E cells was discovered to promote renal tubular EMT and ECM aggregation, and these fibrogenic actions were potentiated by TGF-β1. Notably, RNA-sequencing analysis indicated the possible regulatory role of the PI3K/AKT signaling pathway in Sox9-mediated renal tubular EMT and ECM aggregation. It was further demonstrated that the expression levels of phosphorylated AKT were upregulated in NRK-52E cells overexpressing Sox9, while the PI3K inhibitors, LY29002 and wortmannin, inhibited the renal tubular EMT and ECM aggregation induced by the overexpression of Sox9 in NEK-52E cells. In conclusion, the findings of the present study suggested that Sox9 may serve a profibrotic role in the development of renal tubular EMT and ECM aggregation via the PI3K/AKT signaling pathway. Therefore, Sox9 may be considered as a promising target for treating renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Henoch-Schönlein purpura nephritis (HSPN) is the principal cause of morbidity and mortality in children with Henoch-Schönlein purpura (HSP). However, the criteria for risk assessment currently used is not satisfactory. The urine proteome may provide important clues to indicate the development of HSPN. Methods: Here, we detected and compared the urine proteome of patients with HSPN and healthy controls by liquid chromatography-tandem mass spectrometry (LC–MS/MS) in the data-independent acquisition (DIA) mode. The differentially expressed proteins were analysed by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. For validation, enzyme-linked immunosorbent assay (ELISA) was used to analyse the selected proteins. Results: A total of 125 proteins (29 upregulated and 96 downregulated) were found to be differentially expressed in children with HSPN compared with the controls. Forty-one proteins were predicted to have direct interactions. The enriched pathways mainly included focal adhesion, cell adhesion molecules, the PI3K-Akt signalling pathway, ECM-receptor interactions and so on. Cell adhesion related to the pathogenesis of HSPN was the main biological process identified in this study. The decrease in two proteins (integrin beta-1 and tenascin) was validated by ELISA. Conclusions: Our study provides new insights into the assessment of HSPN progression in children, as well as new potential biomarkers. The data confirm the value of the urinary proteome in capturing the emergence of HSPN. [ABSTRACT FROM AUTHOR]

Previously, we reported that magnetic stimulation of carotid sinus (MSCS) could lower arterial pressure in rabbits. In this randomized, sham-controlled pilot study, we evaluated the effects of MSCS on blood pressure in pre-hypertensive and hypertensive subjects. A total of 15 subjects with blood pressure higher than 130/80 mm Hg were randomized to receive sham or 1Hz MSCS. The changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MAP) during treatment were compared between groups. The heart rate variability (HRV) and baroreflex sensitivity (BRS) before, during, and after treatments were analyzed. Reduction of SBP was significantly greater in subjects with MSCS than those with sham stimulation (6.6 ± 0.4 vs -2.5 ± 0.4 mm Hg, P < 0.001). Reduction of DBP was significantly greater in subjects with MSCS than those with sham stimulation (1.2 ± 0.2 vs -2.8 ± 0.2 mm Hg, P < 0.001). Reduction of MAP was significantly greater in subjects with MSCS than those with sham stimulation (1.4 ± 0.3 mm Hg vs -4.0 ± 0.3 mm Hg, P < 0.001). Reduction of HR was significantly greater in subjects with MSCS than those with sham stimulation (0.5 ± 0.5 vs -1.9 ± 0.3 beats/min, P = 0.002). BRS increased from 6.85 ± 0.77 to 8.79 ± 0.95 ms/mm Hg after MSCS compared with that at baseline (P = 0.027). Thus, MSCS can lower blood pressure and heart rate in pre-hypertensive and hypertensive subject, warranting further study for establishing MSCS as a treatment for hypertension. [ABSTRACT FROM AUTHOR]

Background Our previous study showed a set of increased miRNAs in serum or urine from nephrotic syndrome children. In this study, we investigated the renal expression of these miRNAs in nephrotic children and explored their role in pathogenesis and as potential indicators to differentiate subtypes of kidney diseases. Methods We enrolled 52 children with six different subtypes of nephropathy, and 8 normal kidney tissues were used as controls. RT-qPCR was used to quantify the expression of miR-191, miR-151-3p, miR-150, miR-30a-5p and miR-19b in renal tissues. Results miR-191 and miR-151-3p exhibited significantly higher and lower intrarenal expression in all six subtypes of kidney diseases compared to controls. miR-19b was upregulated in three subtypes, and miR-30a-5p and miR-150 were downregulated in two and four subtypes, respectively. The intrarenal expression of miR-150 was significantly different between minimal change disease (MCD) and some other subtypes. The renal levels of these miRNAs correlated significantly with some renal functions and immune parameters. Bioinformatics showed that some target genes of these miRNAs were associated with immune and renal pathological changes. Conclusions These five miRNAs may be involved in the pathogenesis of nephropathy in children. miR-150 is a potential typing indictor to differentiate MCD from other nephropathy subtypes. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic (HI) brain injury is a serious injury caused by various perinatal factors, which has become a heavy mental burden to the family. The molecular mechanism underlying neonatal hypoxic-ischemic brain injury remains largely unknown. Human bone marrow mesenchymal stem cells (hBMSCs) have caused wide public concern due to the immunomodulatory properties. Exosomes can polarize human microglia and thus changed it into an anti-inflammatory phenotype to reduce the release of pro-inflammatory factors. However, it is unclear whether hBMSCs-exosomes have effect on neonatal hypoxic-ischemic brain injury. In this study, we aimed at investigating the role of hBMSCs-exosomes in regulating immune response and nerve injury in neonatal hypoxic-ischemic brain damage model. In the research, we identified the exosome secretion of hBMSCs could transferred into human microglia (HMC). Moreover, we determined the importance of hBMSCs-exosomes in regulating HMC polarization and inflammatory response. Our research findings might provide a new insight into slowing the disease progression of neonatal hypoxic-ischemic brain injury. [ABSTRACT FROM AUTHOR]

Abstract: Background: The complexes of β2-glycoprotein I (β2-GPI) with lipoprotein(a) [β2-GPI-Lp(a)] exist in human circulation and are increased in serum from patients with some autoimmune diseases. This study aims to investigate the concentration of β2-GPI-Lp(a) in serum of children with idiopathic nephrotic syndrome (NS) and its relationship with serum lipids, oxidized lipoprotein and renal function parameters to explore the potential of the complexes as an additional marker for evaluating pediatric NS. Methods: Serum concentrations of β2-GPI-Lp(a) complexes and oxidized Lp(a) [ox-Lp(a)] were measured by “Sandwich” ELISAs in 80 NS children and 82 age/sex-matched healthy controls. The levels of serum lipids and kidney parameters were also determined. Multivariate logistic regression analysis was performed to identify correlate of β2-GPI-Lp(a) and NS. Results: The serum concentrations of β2-GPI-Lp(a) complexes in children with NS were significantly higher than those in controls (median 0.95U/ml vs 0.28U/ml, P <0.0001). Ox-Lp(a) levels were also markedly elevated (median 14.55mg/l vs 2.60mg/l, P <0.0001] in NS children. The concentrations of β2-GPI-Lp(a) were positively correlated with ox-Lp(a) (r =0.246, P =0.028), but not with Lp(a) level, and the concentrations of ox-Lp(a) were positively related with Lp(a) (r =0.301, P =0.007) in NS children. Multivariate logistic regression analysis identified a positive association between NS and β2-GPI-Lp(a) (OR=13.694, 95% CI 6.400–29.299, P <0.0001), after adjusting for kidney function parameters, serum lipids and ox-Lp(a). Conclusions: Elevated β2-GPI-Lp(a) level was an independent and significant risk factor for pediatric NS and, enhanced Lp(a) oxidation partly contributes to the formation of β2-GPI-Lp(a) complexes. [Copyright &y& Elsevier]